Journal Article

A novel small molecule RAD51 inactivator overcomes imatinib‐resistance in chronic myeloid leukaemia

Li, Guideng, Bhatia, Ravi, Chamberlin, A. Richard, Goldblatt, Erin, Zhu, Jiewen, Qiu, Xiao‐Long, Hu, Chun‐Mei, Wu, Guikai, Chen, Phang‐Lang, Lin, Xiaoqin, Lee, Wen‐Hwa, Konig, Heiko, Zhou, Longen, Chen, Chi‐Fen

2013

Overview

RAD51 recombinase activity plays a critical role for cancer cell proliferation and survival, and often contributes to drug‐resistance. Abnormally elevated RAD51 function and hyperactive homologous recombination (HR) rates have been found in a panel of cancers, including breast cancer and chronic myeloid leukaemia (CML). Directly targeting RAD51 and attenuating the deregulated RAD51 activity has therefore been proposed as an alternative and supplementary strategy for cancer treatment. Here we show that a newly identified small molecule, IBR2, disrupts RAD51 multimerization, accelerates proteasome‐mediated RAD51 protein degradation, reduces ionizing radiation‐induced RAD51 foci formation, impairs HR, inhibits cancer cell growth and induces apoptosis. In a murine imatinib‐resistant CML model bearing the T315I Bcr‐abl mutation, IBR2, but not imatinib, significantly prolonged animal survival. Moreover, IBR2 effectively inhibits the proliferation of CD34 + progenitor cells from CML patients resistant to known BCR‐ABL inhibitors. Therefore, small molecule inhibitors of RAD51 may suggest a novel class of broad‐spectrum therapeutics for difficult‐to‐treat cancers. Graphical Abstract A newly identified RAD51 inhibitor leading to degradation of RAD51 via the proteasome pathway inhibits cancer cell survival and greatly increases life spans in a mouse chronic myeloid leukaemia model.

• Publisher: Nature Publishing Group UK,WILEY‐VCH Verlag,EMBO Press,WILEY-VCH Verlag,Springer Nature
• Subject: Animals / Antineoplastic Agents - metabolism / Antineoplastic Agents - pharmacology / Apoptosis / Apoptosis - drug effects / BCR-ABL protein / Benzamides - pharmacology / Binding Sites / Bone marrow / Breast cancer / cancer / Cancer therapies / CD34 antigen / Cell cycle / Cell Line, Tumor / Cell proliferation / Cell Proliferation - drug effects / Cell survival / Chronic myeloid leukemia / CML / Deoxyribonucleic acid / DNA / DNA damage / Dose-Response Relationship, Drug / Drug Resistance, Neoplasm - genetics / Experiments / Female / Fusion Proteins, bcr-abl - antagonists & inhibitors / Fusion Proteins, bcr-abl - genetics / Gene Expression Regulation, Neoplastic - drug effects / Granulocytes / Homologous recombination / Homologous Recombination - drug effects / Humans / Imatinib / Imatinib Mesylate / Indoles - metabolism / Indoles - pharmacology / inhibitor / Inhibitor drugs / Ionizing radiation / Kinases / Leukemia / Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy / Leukemia, Myelogenous, Chronic, BCR-ABL Positive - enzymology / Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics / Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology / Medical research / Mice / Mice, Inbred NOD / Mice, SCID / Molecular Docking Simulation / Mutation / Neoplastic Stem Cells - drug effects / Neoplastic Stem Cells - pathology / Piperazines - pharmacology / Progenitor cells / Proteasome Endopeptidase Complex - metabolism / Proteasome Inhibitors - metabolism / Proteasome Inhibitors - pharmacology / Proteasomes / Protein Kinase Inhibitors - pharmacology / Protein Multimerization / Protein Processing, Post-Translational / Protein-Tyrosine Kinases - antagonists & inhibitors / Protein-Tyrosine Kinases - genetics / Pyrimidines - pharmacology / RAD51 / Rad51 protein / Rad51 Recombinase - antagonists & inhibitors / Rad51 Recombinase - chemistry / Rad51 Recombinase - genetics / Rad51 Recombinase - metabolism / Recombinase / Research Article / RNA Interference / small molecule / Stem cells / Survival analysis / Targeted cancer therapy / Tetrahydroisoquinolines - metabolism / Tetrahydroisoquinolines - pharmacology / Time Factors / Transfection / Tumor Burden - drug effects